The mitochondrial form of aldehyde dehydrogenase participates in multiple metabolic pathways in humans, including the metabolism of endogenous and biogenic aldehydes, most notably acetaldehyde during ethanol metabolism, and as the bioactivator of nitroglycerin. Nitroglycerin or glycerol trinitrate (GTN) is a potent vasodilator due to its ability to promote the relaxation of smooth muscle cells in the vasculature through the generation of intracellular nitric oxide. The National Institute of Alcohol Abuse and Alcoholism estimates the prevalence of alcohol abuse at just over 4.6% of the general population (~9.6 million) and of frank alcohol dependency at just over 3.8% of the population (~7.9 million) [3]. The National Heart, Lung and Blood Institute and the American Heart Association estimate that approximately 6.5 million people in the US suffer from the general symptoms of angina, which puts the prevalence of the disease just over 2% of the population. Thus, there is a potential for a large fraction of the US population and even larger population in the world to be impacted by progress toward improving our understanding of the role(s) aldehyde dehydrogenase plays in this area. In particular, recent studies have demonstrated that a significant fraction of the East Asian population exhibit reduced efficacy of GTN treatment due to the common polymorphism, ALDH2*2. Structural work in our laboratory has shown that the principal mechanism by which the substitution of Glu487 by Lys (E487K) in the ALDH2*2 variant affects activity is through a loss of structural integrity in the areas surrounding the coenzyme-binding and active sites. Consequently, the enzyme is essentially inactive in vivo because the intracellular concentrations of the coenzyme are too low to support activity for ethanol metabolism and GTN bioactivation. Recent work in the laboratory of our collaborator Dr. Daria Mochly-Rosen, with contributions in enzymology and structural biology from our laboratory, has identified a small molecule activator that restores near wild-type activity to the ALDH2*2 variant. With this as the basis for a new set of studies, our overriding hypothesis is that the unique aspects of catalysis in ALDH2, the high prevalence of the ALDH2*2 allele and their roles in alcohol metabolism and cardiovascular disease will permit the discovery and design of selective agents that will enable the manipulation of ALDH2 activity in a controlled manner to maximize the benefit to specific disease states, while minimizing the impact to other metabolic pathways in which ALDH2 participates. PUBLIC HEALTH RELEVANCE: A large fraction of one's ability to metabolize alcohol, as well as to respond to nitroglycerin treatment for the symptoms of angina is related to the ability of aldehyde dehydrogenase (ALDH2) to catalyze the metabolic conversions of these substrates. Approximately 50% of individuals from East Asian populations harbor an inactive allele of aldehyde dehydrogenase that severely reduces an individual's ability to tolerate alcohol consumption and is, thus, protective for alcoholism. In addition, this same population shows reduced efficacy of nitroglycerin in angina treatment regimens. This application is focused on the development of novel and selective modulators of ALDH2 activity such that specific outcomes associated with changes in ALDH2 activity can be maximized.